Due to disagreements over how technology should be controlled in the wasteland, the Brotherhood of Steel waged a long and bloody war against the NCR. Despite superior equipment and training, the Brotherhood went into retreat.

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The following is based on Van Buren and has not been confirmed by canon sources.

By 2231, Jeremy Maxson had assumed the position of Brotherhood High Elder. In addition to wanting to expand Brotherhood operations eastward, he was much more aggressive in his "hoarding" of pre-War technology. He wanted to restore the power of the Brotherhood by wresting all advanced tech from the hands of "lesser people" by any means necessary. Naturally, this led to disputes with the NCR, which had always been in favor of using advanced technology for the benefit of society (at least, according to Thomas Moore, an NCR citizen, which is what he saw as the NCR's justification for trying to annex Vault City). Sometime after the destruction of the Enclave in 2242, a war broke out between the Brotherhood and the NCR. The exact year is unknown.

The Brotherhood enjoyed a considerable advantage during the early years of the war, as their advanced technology and high standards of training allowed them to inflict tremendous losses on the NCR's military. However, the NCR had a far larger pool of manpower from which to draw troops, while the Brotherhood remained a selective organization, allowing the NCR to easily replace its losses while the Brotherhood became desperate. The Brotherhood fought fiercely, but in the end the NCR's numbers prevailed, and the Brotherhood forces were overwhelmed, forcing them into hiding. Having lost the surface, the Brotherhood prepared themselves to fight to the death as the NCR began to invade their bunkers.

As the Mojave Chapter of the Brotherhood of Steel operated freely among the wastes around New Vegas for several years, they were extremely frustrated when the NCR dispatched troops to the Mojave, although they initially restrained themselves from getting involved in the war. In 2274, the NCR set its sights on the Mojave chapter of the Brotherhood of Steel, led by Elder Elijah, and sought control of their main base, HELIOS One. In 2276, the NCR attacked HELIOS One and Elijah ordered his troops to protect the facility. After taking heavy losses, the Brotherhood retreated to Hidden Valley and have since remained in exile. The NCR success at HELIOS One is credited to their superior numbers (a 20:1 ratio), and the difficulty of defending the location.

As of 2281, the war in the Core Region is still ongoing[1], but the status of the Brotherhood of Steel is unknown. The Mojave chapter is still hiding in the Hidden Valley bunker, where former Paladin Nolan McNamara (in light of Elijah's disappearance following the battle) took the role of Elder upon himself, and placed the bunker under lockdown, stranding Brotherhood stragglers and ceasing contact with the outside world. Since then the Brotherhood's presence in the Mojave Wasteland has been confined to only a few scouting missions.

The NCR held the power plant, but were unable to get it up and running. Its lack of a proper power output later made it a low-priority target for Caesar's Legion. While many believe the Brotherhood to be dead in the Mojave, some in the NCR, like Colonel Moore, suspect otherwise. A major decider of the war in the Mojave is the Courier, who is preparing for the Second Battle of Hoover Dam. If working for Robert House, Caesar's Legion, or the NCR, they will order the eradication of the chapter. The Legion however can be convinced to spare the Brotherhood in the short term on the account that they will cause trouble for the NCR in the rear by taking back HELIOS One. However, the Legion will quickly turn on and overwhelm them just after they do. The NCR, too, wishes for the Courier to kill them, but is willing to create a truce with the Brotherhood in exchange for aid against the Legion, even though this angers some. Unlike with the Legion however, the NCR will stay true to their word, as will the Brotherhood to theirs.

While Colonel Moore states she has survived four tours against the Brotherhood of Steel in California, the results of these battles are unknown, and there is currently only one recorded battle in the war, Operation: Sunburst.